Chemistry and Physics Faculty Articles
Document Type
Article
Publication Date
4-2-2020
Publication Title
International Journal of Molecular Sciences
Keywords
Aldosterone, Cardiac myocyte, G protein-coupled receptor kinase, G protein-coupled estrogen receptor, Mineralocorticoid receptor, Signal transduction
ISSN
1661-6596
Volume
21
Issue/No.
8
First Page
2868
Abstract
Aldosterone (Aldo), when overproduced, is a cardiotoxic hormone underlying heart failure and hypertension. Aldo exerts damaging effects via the mineralocorticoid receptor (MR) but also activates the antiapoptotic G protein-coupled estrogen receptor (GPER) in the heart. G protein-coupled receptor (GPCR)-kinase (GRK)-2 and -5 are the most abundant cardiac GRKs and phosphorylate GPCRs as well as non-GPCR substrates. Herein, we investigated whether they phosphorylate and regulate cardiac MR and GPER. To this end, we used the cardiomyocyte cell line H9c2 and adult rat ventricular myocytes (ARVMs), in which we manipulated GRK5 protein levels via clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and GRK2 activity via pharmacological inhibition. We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER. In H9c2 cardiomyocytes, GRK5 interacts with and phosphorylates the MR upon β2-adrenergic receptor (AR) activation. In contrast, GRK2 opposes agonist-activated GPER signaling. Importantly, GRK5-dependent MR phosphorylation of the MR inhibits transcriptional activity, since aldosterone-induced gene transcription is markedly suppressed in GRK5-overexpressing cardiomyocytes. Conversely, GRK5 gene deletion augments cardiac MR transcriptional activity. β2AR-stimulated GRK5 phosphorylates and inhibits the MR also in ARVMs. Additionally, GRK5 is necessary for the protective effects of the MR antagonist drug eplerenone against Aldo-induced apoptosis and oxidative stress in ARVMs. In conclusion, GRK5 blocks the cardiotoxic MR-dependent effects of Aldo in the heart, whereas GRK2 may hinder beneficial effects of Aldo through GPER. Thus, cardiac GRK5 stimulation (e.g., via β2AR activation) might be of therapeutic value for heart disease treatment via boosting the efficacy of MR antagonists against Aldo-mediated cardiac injury.
Additional Comments
American Heart Association grant #: 09SDG2010138
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
NSUWorks Citation
Maning, J., McCrink, K. A., Pollard, C. M., Desimine, V., Ghandour, J., Perez, A., Cora, N., Ferraino, K. E., Parker, B., Brill, A., Aukszi, B., & Lymperopoulos, A. (2020). Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition. International Journal of Molecular Sciences, 21, (8), 2868 - . https://doi.org/10.3390/ijms21082868. Retrieved from https://nsuworks.nova.edu/cnso_chemphys_facarticles/275
DOI
10.3390/ijms21082868
Comments
©2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).